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Patients with chronic inflammatory disorders such as psoriasis have an increased risk of cardiovascular disease and elevated levels of LL37, a cathelicidin host defense peptide that has both antimicrobial and proinflammatory properties. To explore whether LL37 could contribute to the risk of heart disease, we examined its effects on lipoprotein metabolism and show that LL37 enhanced LDL uptake in macrophages through the LDL receptor (LDLR), scavenger receptor class B member 1 (SR-B1), and CD36. This interaction led to increased cytosolic cholesterol in macrophages and changes in expression of lipid metabolism genes consistent with increased cholesterol uptake. Structure-function analysis and synchrotron small-angle x-ray scattering showed structural determinants of the LL37-LDL complex that underlie its ability to bind its receptors and promote uptake. This function of LDL uptake is unique to cathelicidins from humans and some primates and was not observed with cathelicidins from mice or rabbits. Notably, Apoe-/- mice expressing LL37 developed larger atheroma plaques than did control mice, and a positive correlation between plasma LL37 and oxidized phospholipid on apolipoprotein B (OxPL-apoB) levels was observed in individuals with cardiovascular disease. These findings provide evidence that LDL uptake can be increased via interaction with LL37 and may explain the increased risk of cardiovascular disease associated with chronic inflammatory disorders.

Red blood cell (RBC) shape and deformability are supported by a planar network of short actin filament (F-actin) nodes (∼37 nm length, 15-18 subunits) interconnected by long spectrin strands at the inner surface of the plasma membrane. Spectrin-F-actin network structure underlies quantitative modeling of forces controlling RBC shape, membrane curvature, and deformation, yet the nanoscale organization and dynamics of the F-actin nodes in situ are not well understood. We examined F-actin distribution and dynamics in RBCs using fluorescent-phalloidin labeling of F-actin imaged by multiple microscopy modalities. Total internal reflection fluorescence and Zeiss Airyscan confocal microscopy demonstrate that F-actin is concentrated in multiple brightly stained F-actin foci ∼200-300 nm apart interspersed with dimmer F-actin staining regions. Single molecule stochastic optical reconstruction microscopy imaging of Alexa 647-phalloidin-labeled F-actin and computational analysis also indicates an irregular, nonrandom distribution of F-actin nodes. Treatment of RBCs with latrunculin A and cytochalasin D indicates that F-actin foci distribution depends on actin polymerization, while live cell imaging reveals dynamic local motions of F-actin foci, with lateral movements, appearance and disappearance. Regulation of F-actin node distribution and dynamics via actin assembly/disassembly pathways and/or via local extension and retraction of spectrin strands may provide a new mechanism to control spectrin-F-actin network connectivity, RBC shape, and membrane deformability.

Patients with chronic inflammatory disorders such as psoriasis have an increased risk of cardiovascular disease and elevated levels of LL37, a cathelicidin host defense peptide that has both antimicrobial and proinflammatory properties. To explore whether LL37 could contribute to the risk of heart disease, we examined its effects on lipoprotein metabolism and show that LL37 enhanced LDL uptake in macrophages through the LDL receptor (LDLR), scavenger receptor class B member 1 (SR-B1), and CD36. This interaction led to increased cytosolic cholesterol in macrophages and changes in expression of lipid metabolism genes consistent with increased cholesterol uptake. Structure-function analysis and synchrotron small-angle x-ray scattering showed structural determinants of the LL37-LDL complex that underlie its ability to bind its receptors and promote uptake. This function of LDL uptake is unique to cathelicidins from humans and some primates and was not observed with cathelicidins from mice or rabbits. Notably, [Apoe.sup.-/-] mice expressing LL37 developed larger atheroma plaques than did control mice, and a positive correlation between plasma LL37 and oxidized phospholipid on apolipoprotein B (OxPL-apoB) levels was observed in individuals with cardiovascular disease. These findings provide evidence that LDL uptake can be increased via interaction with LL37 and may explain the increased risk of cardiovascular disease associated with chronic inflammatory disorders., Introduction Atherosclerosis is characterized by lipid accumulation and local inflammation in the arterial vessel wall and is a major cause of cardiovascular diseases such as myocardial infarction and peripheral arterial [...]

Membrane bending is a ubiquitous cellular process that is required for membrane traffic, cell motility, organelle biogenesis, and cell division. Proteins that bind to membranes using specific structural features, such as wedge-like amphipathic helices and crescent-shaped scaffolds, are thought to be the primary drivers of membrane bending. However, many membrane-binding proteins have substantial regions of intrinsic disorder which lack a stable three-dimensional structure. Interestingly, many of these disordered domains have recently been found to form networks stabilized by weak, multivalent contacts, leading to assembly of protein liquid phases on membrane surfaces. Here we ask how membrane-associated protein liquids impact membrane curvature. We find that protein phase separation on the surfaces of synthetic and cell-derived membrane vesicles creates a substantial compressive stress in the plane of the membrane. This stress drives the membrane to bend inward, creating protein-lined membrane tubules. A simple mechanical model of this process accurately predicts the experimentally measured relationship between the rigidity of the membrane and the diameter of the membrane tubules. Discovery of this mechanism, which may be relevant to a broad range of cellular protrusions, illustrates that membrane remodeling is not exclusive to structured scaffolds but can also be driven by the rapidly emerging class of liquid-like protein networks that assemble at membranes.

Dendritic spines are small, bulbous protrusions along the dendrites of neurons and are sites of excitatory postsynaptic activity. The morphology of spines has been implicated in their function in synaptic plasticity and their shapes have been well-characterized, but the potential mechanics underlying their shape development and maintenance have not yet been fully understood. In this work, we explore the mechanical principles that could underlie specific shapes using a minimal biophysical model of membrane-actin interactions. Using this model, we first identify the possible force regimes that give rise to the classic spine shapes-stubby, filopodia, thin, and mushroom-shaped spines. We also use this model to investigate how the spine neck might be stabilized using periodic rings of actin or associated proteins. Finally, we use this model to predict that the cooperation between force generation and ring structures can regulate the energy landscape of spine shapes across a wide range of tensions. Thus, our study provides insights into how mechanical aspects of actin-mediated force generation and tension can play critical roles in spine shape maintenance.

The biconcave disk shape of the mammalian red blood cell (RBC) is unique to the RBC and is vital for its circulatory function. Due to the absence of a transcellular cytoskeleton, RBC shape is determined by the membrane skeleton, a network of actin filaments cross-linked by spectrin and attached to membrane proteins. While the physical properties of a uniformly distributed actin network interacting with the lipid bilayer membrane have been assumed to control RBC shape, recent experiments reveal that RBC biconcave shape also depends on the contractile activity of nonmuscle myosin IIA (NMIIA) motor proteins. Here, we use the classical Helfrich-Canham model for the RBC membrane to test the role of heterogeneous force distributions along the membrane and mimic the contractile activity of sparsely distributed NMIIA filaments. By incorporating this additional contribution to the Helfrich-Canham energy, we find that the RBC biconcave shape depends on the ratio of forces per unit volume in the dimple and rim regions of the RBC. Experimental measurements of NMIIA densities at the dimple and rim validate our prediction that (a) membrane forces must be non-uniform along the RBC membrane and (b) the force density must be larger in the dimple than the rim to produce the observed membrane curvatures. Furthermore, we predict that RBC membrane tension and the orientation of the applied forces play important roles in regulating this force-shape landscape. Our findings of heterogeneous force distributions on the plasma membrane for RBC shape maintenance may also have implications for shape maintenance in different cell types.

Membrane nanotubes are dynamic structures that may connect cells over long distances. Nanotubes are typically thin cylindrical tubes, but they may occasionally have a beaded architecture along the tube. In this paper, we study the role of membrane mechanics in governing the architecture of these tubes and show that the formation of bead-like structures along the nanotubes can result from local heterogeneities in the membrane either due to protein aggregation or due to membrane composition. We present numerical results that predict how membrane properties, protein density, and local tension compete to create a phase space that governs the morphology of a nanotube. We also find that there exists a discontinuity in the energy that impedes two beads from fusing. These results suggest that the membrane-protein interaction, membrane composition, and membrane tension closely govern the tube radius, number of beads, and the bead morphology.

To alter and adjust the shape of the plasma membrane, cells harness various mechanisms of curvature generation. Many of these curvature generation mechanisms rely on the interactions between peripheral membrane proteins, integral membrane proteins, and lipids in the bilayer membrane. Mathematical and computational modeling of membrane curvature generation has provided great insights into the physics underlying these processes. However, one of the challenges in modeling these processes is identifying the suitable constitutive relationships that describe the membrane free energy including protein distribution and curvature generation capability. Here, we review some of the commonly used continuum elastic membrane models that have been developed for this purpose and discuss their applications. Finally, we address some fundamental challenges that future theoretical methods need to overcome to push the boundaries of current model applications.

To alter and adjust the shape of the plasma membrane, cells harness various mechanisms of curvature generation. Many of these curvature generation mechanisms rely on the interactions between peripheral membrane proteins, integral membrane proteins, and lipids in the bilayer membrane. Mathematical and computational modeling of membrane curvature generation has provided great insights into the physics underlying these processes. However, one of the challenges in modeling these processes is identifying the suitable constitutive relationships that describe the membrane free energy including protein distribution and curvature generation capability. Here, we review some of the commonly used continuum elastic membrane models that have been developed for this purpose and discuss their applications. Finally, we address some fundamental challenges that future theoretical methods need to overcome to push the boundaries of current model applications.

A critical step in how malaria parasites invade red blood cells (RBCs) is the wrapping of the membrane around the egg-shaped merozoites. Recent experiments have revealed that RBCs can be protected from malaria invasion by high membrane tension. While cellular and biochemical aspects of parasite actomyosin motor forces during the malaria invasion have been well studied, the important role of the biophysical forces induced by the RBC membrane-cytoskeleton composite has not yet been fully understood. In this study, we use a theoretical model for lipid bilayer mechanics, cytoskeleton deformation, and membrane-merozoite interactions to systematically investigate the influence of effective RBC membrane tension, which includes contributions from the lipid bilayer tension, spontaneous tension, interfacial tension, and the resistance of cytoskeleton against shear deformation on the progression of membrane wrapping during the process of malaria invasion. Our model reveals that this effective membrane tension creates a wrapping energy barrier for a complete merozoite entry. We calculate the tension threshold required to impede the malaria invasion. We find that the tension threshold is a nonmonotonic function of spontaneous tension and undergoes a sharp transition from large to small values as the magnitude of interfacial tension increases. We also predict that the physical properties of the RBC cytoskeleton layer—particularly the resting length of the cytoskeleton—play key roles in specifying the degree of the membrane wrapping. We also found that the shear energy of cytoskeleton deformation diverges at the full wrapping state, suggesting the local disassembly of the cytoskeleton is required to complete the merozoite entry. Additionally, using our theoretical framework, we predict the landscape of myosin-mediated forces and the physical properties of the RBC membrane in regulating successful malaria invasion. Our findings on the crucial role of RBC membrane tension in inhibiting malaria invasion can have implications for developing novel antimalarial therapeutic or vaccine-based strategies. Author summary: RBC membrane tension plays an important role in regulating RBC shape and functionality. In particular, recent experimental studies have shown that elevated RBC membrane tension protects against severe malaria infection. In this study, we sought to identify how different contributions to the effective membrane tension can contribute to this mechanically driven protection against malaria invasion. Using a mathematical model, we derived a relationship between the effective tension of the RBC membrane—comprising a lipid bilayer and a cytoskeleton layer– and the degree of membrane wrapping during malaria invasion. Our model shows that the shear resistance of the RBC cytoskeleton plays an important role in inhibiting malaria invasion. Our findings can be generalized to the role of cell membrane mechanics in many wrapping phenomena providing insight into the crucial contributions of the host-cell membrane in protection against severe infections. [ABSTRACT FROM AUTHOR]

Brain-inspired computing models have shown great potential to outperform today's deep learning solutions in terms of robustness and energy efficiency. Particularly, Hyper-Dimensional Computing (HDC) has shown promising results in enabling efficient and robust cognitive learning. In this study, we exploit HDC as an alternative computational model that mimics important brain functionalities toward high-efficiency and noise-tolerant neuromorphic computing. We present EventHD, an end-to-end learning framework based on HDC for robust, efficient learning from neuromorphic sensors. We first introduce a spatial and temporal encoding scheme to map event-based neuromorphic data into high-dimensional space. Then, we leverage HDC mathematics to support learning and cognitive tasks over encoded data, such as information association and memorization. EventHD also provides a notion of confidence for each prediction, thus enabling self-learning from unlabeled data. We evaluate EventHD efficiency over data collected fromDynamic Vision Sensor (DVS) sensors. Our results indicate that EventHD can provide online learning and cognitive support while operating over raw DVS data without using the costly preprocessing step. In terms of efficiency, EventHD provides 14.2× faster and 19.8× higher energy efficiency than state-of-the-art learning algorithms while improving the computational robustness by 5.9×. [ABSTRACT FROM AUTHOR]

Membrane bending is a ubiquitous cellular process that is required for membrane traffic, cell motility, organelle biogenesis, and cell division. Proteins that bind to membranes using specific structural features, such as wedge-like amphipathic helices and crescent-shaped scaffolds, are thought to be the primary drivers of membrane bending. However, many membrane-binding proteins have substantial regions of intrinsic disorder which lack a stable three-dimensional structure. Interestingly, many of these disordered domains have recently been found to form networks stabilized by weak, multivalent contacts, leading to assembly of protein liquid phases on membrane surfaces. Here we ask how membrane-associated protein liquids impact membrane curvature. We find that protein phase separation on the surfaces of synthetic and cell-derived membrane vesicles creates a substantial compressive stress in the plane of the membrane. This stress drives the membrane to bend inward, creating protein-lined membrane tubules. A simple mechanical model of this process accurately predicts the experimentally measured relationship between the rigidity of the membrane and the diameter of the membrane tubules. Discovery of this mechanism, which may be relevant to a broad range of cellular protrusions, illustrates that membrane remodeling is not exclusive to structured scaffolds but can also be driven by the rapidly emerging class of liquid-like protein networks that assemble at membranes. [ABSTRACT FROM AUTHOR]

Mitochondrial fission is controlled by dynamin proteins, the dysregulation of which is correlated with diverse diseases. Fission dynamins are GTP hydrolysis-driven mechanoenzymes that self-oligomerize into helical structures that constrict membrane to achieve fission, but details are not well understood. However, dynamins can also remodel membranes by inducing negative Gaussian curvature, the type of curvature required for completion of fission. Here, we examine how these drastically different mechanisms synergistically exert their influences on a membrane, via a mechanical model calibrated with small-angle X-ray scattering structural data. We find that free dynamin can trigger a "snap-through instability" that enforces a shape transition from an oligomer-confined cylindrical membrane to a drastically narrower catenoid-shaped neck within the spontaneous hemi-fission regime, in a manner that depends critically on the length of the confined tube. These results indicate how the combination of dynamin assembly, and paradoxically disassembly, can lead to diverse pathways to scission.

Classically, chemokines coordinate leukocyte trafficking during immune responses; however, many chemokines have also been reported to possess direct antibacterial activity in vitro. Yet, the bacterial killing mechanism of chemokines and the biochemical properties that define which members of the chemokine superfamily are antimicrobial remain poorly understood. Here we report that the antimicrobial activity of chemokines is defined by their ability to bind phosphatidylglycerol and cardiolipin, two anionic phospholipids commonly found in the bacterial plasma membrane. We show that only chemokines able to bind these two phospholipids kill Escherichia coli and Staphylococcus aureus and that they exert rapid bacteriostatic and bactericidal effects against E. coli with a higher potency than the antimicrobial peptide beta-defensin 3. Furthermore, our data support that bacterial membrane cardiolipin facilitates the antimicrobial action of chemokines. Both biochemical and genetic interference with the chemokine-cardiolipin interaction impaired microbial growth arrest, bacterial killing, and membrane disruption by chemokines. Moreover, unlike conventional antibiotics, E. coli failed to develop resistance when placed under increasing antimicrobial chemokine pressure in vitro. Thus, we have identified cardiolipin and phosphatidylglycerol as novel binding partners for chemokines responsible for chemokine antimicrobial action. Our results provide proof of principle for developing chemokines as novel antibiotics resistant to bacterial antimicrobial resistance mechanisms., Competing Interests: CONFLICT OF INTEREST B.F.V has ownership interests in Protein Foundry, LLC and XLock Biosciences, Inc. All other authors declare no competing interests.